CROI 2019 Abstract eBook
410 PLASMA (1 → 3)-Β-D-GLUCAN LEVELS CORRELATE WITH NEUROCOGNITIVE PERFORMANCE IN HIV
1 University of Hawaii, Honolulu, HI, USA, 2 Thai Red Cross AIDS Research Center, Bangkok, Thailand, 3 University of California San Francisco, San Francisco, CA, USA, 4 University of Missouri St Louis, St Louis, MO, USA, 5 Armed Forces Research Institute of Medical Sciences in Bangkok, Bangkok, Thailand Background: Monocytes are involved in HIV pathogenesis, persistence, and are associated with adverse clinical outcomes. We previously revealed in monocytes the identification of an epigenetic footprint of HIV-related cognitive impairment in chronic infection (PMCID: PMC5024304). Yet, knowledge about epigenetic changes during acute HIV infection (AHI) in monocytes, the effects of early initiation of combination anti-retroviral therapy (cART), and the implications on CNS outcomes remains unknown. Methods: We investigated early HIV-related DNA methylation changes in highly purified monocytes from AHI adults initiating early ART in a prospective study (RV254/ SEARCH010) and uninfected controls (RV304/ SEARCH013). DNA methylation was measured genome-wide using the Illumina HumanMethylationEPIC array. We also examined DNA methylation changes longitudinally during AHI at entry and post-cART. Results: We examined 15 AHI adults (n=6 Fiebig stage (F) I/II and n=9 (FIII) with median days of infection of 17.5 days (baseline). Twelve adults were examined after initiating cART up to 48 weeks (post-cART). Matched HIV- uninfected adults (n=8) served as controls. In cell sorted purified monocytes obtained from peripheral blood, we observed 2,847 CpG sites showing absolute mean differences in methylation greater than 5% between during AHI and uninfected participants (Δβ-value > |0.05| and significant at FDR adjusted P < 0.05). The majority (94.55%) of sites were hypomethylated in AHI compared to uninfected and related to genes involved in the type I interferon signaling pathway and activating transcription factor binding pathway. We utilized a paired differential methylation analysis of donors at baseline and post-cART and observed 350 CpG sites showing absolute mean differences in methylation greater than 5% (Δβ-value > |0.05| and significant at FDR adjusted P < 0.05). We evaluated if the HIV-related DNA methylation changes in monocytes were impacted by immediate ART and observed that less than 3% (76 methylation sites) of the 2,847 HIV-related CpGs were overlapping with the 350 CpGs impacted by cART treatment. Conclusion: HIV-related DNA methylation changes were identified as early as FI/II in AHI and early cART minimally restored these changes suggesting HIV embeds an indelible epigenetic memory. Further investigation is needed to determine whether HIV epigenetic changes relate to viral persistence, residual inflammation or CNS decline that are seen in chronic infection.
Martin Hoenigl 1 , Scott L. Letendre 1 , Jennifer Iudicello 1 , Donald Franklin 1 , Magali Porrachia 2 , Milenka Vargas 2 , Ronald J. Ellis 1 , Malcolm Finkelman 3 , Sara Gianella 2 1 University of California San Diego, San Diego, CA, USA, 2 University of California San Diego, La Jolla, CA, USA, 3 Associates of Cape Cod, Inc, Falmouth, MA, USA Background: Although antiretroviral therapy (ART) has improved survival and morbidity, people living with HIV (PLWH) have higher rates of non-AIDS disorders, such as neurocognitive (NC) impairment (NCI), than the general population. (1-3)-b-D-glucan (BDG) is a fungal cell wall component which – in the absence of fungal infections – serves as biomarker for gut barrier integrity failure and microbial translocation. The objective of this study was to determine whether higher plasma and cerebrospinal fluid (CSF) levels of BDG are associated with NCI in PLWH. Methods: Paired blood and CSF samples were collected from 61 PLWH who underwent a NC assessment as part of the prospective CHARTER study between 2005- 2015. Raw NC test scores were converted to ddemographically- adjusted T-scores and used to derive a Global T-score (higher scores=better performance). Individual T-scores were also converted to deficit scores and averaged to derive a global deficit score (GDS) which was used to classify NCI (i.e., GDS≥0.5). Specimens were stored at -80°C within 90 minutes of collection. BDG was measured using the Fungitell assay (Associates of Cape Cod, Inc.) and soluble urokinase plasminogen activator receptor (suPAR; marker of monocyte activation and chronic inflammation) using the suPARnostic assay (ViroGates, Copenhagen, Denmark). Blood plasma samples were also tested for sCD14 (marker of monocyte activation), intestinal fatty acid binding protein (IFABP, marker of gut epithelial dysfunction), and blood CD4/CD8 ratio. Spearman’s rho correlation analysis assessed associations between BDG, other biomarkers and NC performance variables. Results: Overall, 58/61 participants had undetectable HIV RNA in blood plasma at the time of sampling. Median BDG level was 18 pg/mL in plasma (range: 2-60 pg/mL) and 20 pg/mL in CSF (range: 0-830 pg/mL). Higher levels of plasma BDG were associated with lower Global T Scores (Spearman rho=-0.32; p=0.013) and NCI (p=0.027, see Figure). A plasma BDG cut-off of >30pg/mL showed 30% sensitivity for NCI and 100% specificity. There was also a trend towards higher CSF BDG levels among those impaired versus unimpaired (p=0.083). No other significant associations were observed between the remaining biomarkers and the NC variables. Plasma levels of BDG correlated significantly with plasma suPAR levels (rho=0.31, p=0.016), but not with other biomarkers. Conclusion: Elevated plasma levels of BDG may be a biomarker for detection of NCI in PLWH on suppressive ART.
411LB NEURON-DERIVED EXOSOMES IDENTIFY COGNITIVE IMPAIRMENT AND GENDER DIFFERENCES IN HIV Lynn Pulliam 1 , Nicole Fernandes 2 , Bing Sun 2 1 University of California San Francisco, San Francisco, CA, USA, 2 San Francisco VA Medical Center, San Francisco, CA, USA Background: Cognitive impairment in chronic well-controlled HIV infection continues to affect up to 60% of individuals. Mechanisms are still unknown but probably associated with continued neuroinflammation. Plasma neuron- derived exosomes (NDE) are a peripheral biomarker for investigating the health
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